Abstract: Heritable changes in gene expression occurring without alterations in gene sequence are referred to as "epigenetic", and dysregulation of this epigenetic signaling underlies several human biological processes and diseases such as cancer. At the center of epigenetic mechanisms are critical chromatin regulatory networks such as DNA methylation and histone post-translational modifications (PTMs). Histone PTMs have been linked to both gene activation and silencing depending on the specific single modification site. Nevertheless, what type of effect distinct combinations of simultaneously occurring histone modifications (Histone Codes) have upon cellular events is poorly understood. The main reason for this lack of knowledge is that robust high- throughput methods for quantitative characterization or even qualitative identification of combinatorial Histone Codes by any biological means do not exist. Our work has addressed this deficiency by developing a novel mass spectrometry based proteomic platform for quantitative molecular level descriptions of combinatorial Histone Code signaling. Our preliminary data reveal that hundreds of distinct Histone Codes exist throughout the human genome, and we plan to apply this approach to discover how dynamic Histone Codes influence gene expression in several types of cancers. We will work towards the goal of taking any defined part of the genome during disease state and accurately quantifying the Histone Codes, detecting any non-histone proteins, and then mapping these back to the specific genomic locations, thereby taking a snapshot of the chromatin landscape during cancer progression. It is currently appreciated that cancer is a disease of both genetic and epigenetic transformations. While genetic causes have been associated with several types of cancers, epigenetic aspects related to histone modifications remain elusive. We believe that comprehension of these altered histone PTM mechanisms at the Histone Code level in these processes may lead to enhanced diagnostics or development of epigenetic therapy beneficial for human health. Public Health Relevance: Aberrant changes in histone modifications have been linked to diseases such as cancer, but currently the technology to detect these changes on a combinatorial multisite level is severely limited. We plan to use novel technology to address this problem to discover histone modification patterns associated with disease progression in several types of cancers, thereby creating initial knowledge that may be beneficial for disease diagnostics or treatment.